This proposal is an initial submission from Jacob D. McGuire, DDS for the Ruth L Kirschstein National Research Service Award (NRSA) for Individual Postdoctoral Fellows (F-32). This award will serve as the platform to complete his doctoral education in the interdisciplinary Oral Biology PhD program at the University of Missouri-Kansas City School of Dentistry. In addition, this award will equip him for a high impact research career as an independent dental researcher. The overall goal of this proposal is to characterize the effect of radiotherapy on enamel associated proteins. The majority of oral cancer patients receive radiotherapy for its anti-cancer and life saving effects. Following irradiation numerous negative oral sequelae develop including enamel loss/shearing. Pathologic enamel loss greatly diminish a patient's quality of life, limit performance of everyday activities; and negatively affect one's psychological and social well-being. Enamel loss/shearing initiates following radiotherapy and progresses over time resulting in partial to complete delamination of enamel from the supporting dentin. Without the protective enamel, exposed dentin decays rapidly and leads to further morbidity. Enamel associated proteins are remnants from developing enamel and are highly concentrated at the dentin-enamel junction (DEJ) in the incisal, cuspal, cervical, and fissure regions. Based on their intraenamel location, they may act as a 'cementing material' by imparting stability to the DEJ and enamel proper. A mechanism to explain why enamel shears at the normally stable junction of the DEJ following radiotherapy has not been elucidated. A potential explanation could be linked to enamel proteins heavily concentrated near the DEJ. We hypothesize that radiotherapy may alter or damage proteins associated with enamel by altering their structural integrity and chemical profile. These structural and chemical changes may affect the stability of the DEJ, resulting in enamel loss observed clinically. The specific aims will 1) characterize the structural integrity of enamel associated proteins before and subsequent to radiotherapy; 2) characterize the chemical profile of enamel associated proteins before and subsequent to radiotherapy. Outcomes of the proposed study have the potential to begin localizing a mechanism contributing to post-radiotherapy enamel loss, which would provide vital knowledge to begin directing development of preventative and restorative treatments for patients post-radiotherapy. PUBLIC HEALTH RELEVANCE: The majority of oral cancer patients receive radiotherapy for its anti-cancer and life saving effects. Following irradiation numerous negative oral sequelae develop including enamel loss/shearing. Our studies will provide understandings of how enamel associated proteins are affected subsequent to radiotherapy, which in turn could begin isolating a mechanism of enamel loss and dentin-enamel junction destabilization.